Mucosal body surfaces, such as the corneal surface, and the surface epithelial lining of body cavities, are potentially useful sites for drug administration. For example, many ophthalmic diseases, such as viral and bacterial infections, and chronic conditions, such as glaucoma, can be treated by topical durg administration to the ocular surface. Other mucosal tissue sites. including the nose. mouth, throat. rectum, vagina, and stomach are also important target areas of direct drug adiministration.
Currently, many ophthalmic drugs are applied in soulution form to the ocular surface. A majon problem with this approach is limited drug uptake, since the drugs solution is rather quickly washed away by tearing action. Because of the rapid clearance, an ophthalmic drugs may have to be adiministered several times a day. The frequent doses which are needed reduce patient compliance, and can be quite uncomfortable for the patient, as in the case of common anti-glaucoma drugs which cause blurred vision for several hours after application.
The retention of a solution-form drugs on the corneal surface can be enhanced by the use of polymers. such as hydroxythylcellulose or methylcellulose, which increase the viscosity of the drug solution. Polymer containing viscous liquids are used, for example, in the treatment of dry eye, to help keep the corneal surface moist. However, with the increased viscosity, very little of the originally applied liquid is retained for more than about an hour, so frequent dosing is necessary.
For body-cavity sites, suppositories are a convenient method for releasing medication to the mucosal tissue over an extended period, and for drug release in the stomach, slow release particles that break down at variable rates are commonly used. Even though suppositories and slow-release particles may give sustained drug release in the region of the mucosa, only a small percentage of the release drug may be taken up by the mucosa, due to rapid drug "clearance" by the normal cavity fluids.
The concept of using liposomes to enhance the delivery of drugs at a mucosal tissue has been proposed, but this approach has been limited heretofore by relatively poor retention of liposomes on mucosal tissue (Lee). Studies conducted in support of the present invention, for example, show that retention of conventional liposomes on an ocular surface is less than about 5% after 1 hour. Thus, even though liposomes have the capability of controlled drug release over a several hour period, this feature has not been exploitable in the past bacause of poor liposome retention at the target site.
Some improvement in liposome retention has been reported for liposome containing charged lipids, such as cholesteryl amine, into liposome. Presumably the increased retention is due to the interaction of the liposome surface positive charges with mucin, a negatively charged glycoprotein which is secreted by and present in the environment of mucosal tissue. Ocular-retention studies performed in support of the present invention show that at a cholesterol amine concentration of 40 mole percent, liposome retention at the end of an hour increases from about 5% for uncharged liposomes to about 10% of the originally applied liposomes. This small increase in enhancement falls short of the increase in liposome retention which would be needed to provide effective drug release several hours after the liposome are applied to the mucosal surface.
Relatively long chain alkyl amines, such as stearylamine, have been used to increase retention of liposomes to ocular mucosa (Schaeffer). However, charged amines of this type tend to be toxic at elevated levels (Yashihare) and therefore cannot be used at molar concentrations that give maximal liposome retention properties. This problem is aggravated in part because the single chain molecules of this type can readily dissociate from the liposome bilayer, and because the molecules themselves tend to destabilize the liposome bilayer structure.